Epinephrine ointment and method of



United States Patent EPINEPHRINE OINTMENT AND METHOD OF PREPARATION THEREOF Harold A. Abramson, New York, N. Y.

No Drawing. Application February 18, 1953, Serial No. 337,679

8 Claims. (Cl. 167-63) My present invention relates, generally, to novel therapeutic compositions and methods of making the same wherein epinephrine, either as the base or as one of the physiologically active salts, is protected and stabilized against oxidation. The invention relates more particularly to epinephrine ointments and ointment bases, and methods of preparing the same, wherein epinephrine is protected against oxidation so that the epinephrine activity remains unimpaired for extended periods under ordinary storage conditions.

Epinephrine base and its physiologically active salts or derivatives, such as epinephrine hydrochloride, epinephrine bitartrate, epinephrine. sulfate and epinephrine borate, are notable for theease with which they decompose or deteriorate. Epinephrine compounds are particularly sensitive to heat and to deterioration by oxidation and exposure to light also tends to hasten decomposition, which is manifested by discoloration or browning of the compounds which are white when in a pure and fresh condition.

Because of the instability of epinephrine on exposure to air, epinephrine compounds are normally packaged and distributed in nitrogen-filled glassampoules in the absence of oxygen. Epinephrine compounds cannot withstand heating and therefore heating of epinephrine compounds is to be avoided.

I have found in accordance with the present invention a method by which medically useful epinephrine compounds may be provided with a protective coating of antioxidant films in such a manner that the epinephrine may be uniformly dispersed and suspended in oily vehicles such as mineral oil, sesame oil, or petrolatum and retain full stability for prolonged periods. The method of this invention involves first dissolving a suitable anti-oxidant in a liquid which is a solvent for the anti-oxidant but in which epinephrine base or its medically useful compounds are insoluble. After such an anti-oxidant solution has been prepared, the epinephrine in powdered form is uniformly dispersed in the solution and the solvent is then evaporated, preferably under reduced pressure without heating. Dryingis discontinued before all of the solvent has completely evaporated so as to leave the residue in a condition in which it is not completely dry or cake solid. The preferred condition of the residue is one which permits it to be easily dispersed and suspended in an oily vehicle such as mineral oil or petrolatum. An ointment or ointment base prepared in this manner and packed in ordinary medical tins will retain its full physiological activity without noticeable deterioration or discoloration at temperatures up to 50 C. for well over a month, and at ordinary room temperatures for well over a year.

An object of the invention is a practical and convenient method whereby medically useful uniform suspensions and dispersions of epinephrine, either as the base or its various physiologically active salts, in oils and ointments may be made and an anti-oxidant for the epinephrine compound incorporated in such a manner that the preparations re- 2 ,735,799 Patented Feb. 21, 1956 tain substantially full epinephrine potency for prolonged periods at ordinary temperatures and conditions.

An object of the present invention is the provision of a method whereby, and compositions wherein, epinephrine in its various physiological forms is stabilized against oxidative-deterioration or spoilage without being packaged in oxygen-free, nitrogen-filled containers or ampoules.

Another object of the invention is the provision of ointments and ointment bases containing epinephrine in one of its physiological forms, which ointments are producible by a convenient, inexpensive method and are safe to use and retain full potency for prolonged periods when stored in ordinary containers such as medical tins or collapsible tubes.

Another object of the invention is the provision of an epinephrine ointment for oil base wherein the epinephrine content is stabilized and protected against oxidation and deterioration due to exposure to air and light and which oils or ointment bases may be used as such or mixed with other ointments or constituents such as coal tar ointments and anesthetic ointments such as benzocaine ointment.

' Still another object of the invention is the provision of epinephrine ointments which are biologically and physiologically active to relieve itching and inflammation on the human skin by virtue of their anti-histaminic and vasoconstrictor actions, and which ointments retain their activity for prolonged periods of time when stored under ordinary conditions in ordinary type containers.

Certain other objects of the invention will, in part, be obvious and will, in part, appear hereinafter.

For a more complete understanding of the nature and scope of the invention, reference may be had to the fol- Example 1 0.1 gram of propyl gallate was dissolved in 20 grams of ether (USP grade). 1 gram of epinephrine (USP) having a particle size of approximately 10 microns or below was added to the ether solution of propyl gallate and the mixture was placed in a tuning fork disintegrator (or a colloid mill or other known type of disintegrator or blender). The solution was left in the disintegrator for approximately 2 minutes during which time the glass beads in the disintegrator sub-divided the clusters of the epinephrine powder into individual particles and reduced the particle size of the individual particles somewhat. The mixture was removed from the disintegrator and placed in a vacuum chamber equipped with a suitable agitator whereby the mixture could be agitated for uniformity while the ether was being evaporated at room temperature. Before the ether had been completely volatilized and removed, drying was discontinued when the residue was slightly moist and not yet hardened or completely dried. The paste was gently pulverized into particles of epinephrine coated with and encased in propyl gallate. Such protective sheaths or coatings of the anti-oxidant formed around the epinephrine particles during evaporation. These particles were suspended in 50 grams of mineral oil and uniformly distributed therein by placing in a known type of blender or disintegrator such as a ball mill, Waring Blendor or a tuning fork disintegrator. The uniform suspension of the epinephrine particles in mineral oil was then uniformly blended with 500 grams of petrolatum to provide an ointment base having an epinephrine concentration of 1 to 500.

Example 2 30 grams of the epinephrine ointment base prepared in accordance with Example 1 was intimately blended with 30 grams of coal tar ointment. The resulting ointment is adapted for treatment of eczema.

Example 3 30 grams of the ointment base prepared in accordance with Example 1 was blended with 30 grams of petrolatum so as to produce an ointment having an epinephrine concentration of l to 1,000 and the resulting ointment was found to be of value in the treatment of pruritis ani, pruritis vulvae, allergic dermatitis, poison ivy and other similar itching dermatoses of the skin where the skin was broken. This ointment was also of value in the treatment of vasomotor rhinitis. This ointment was placed in ordinary ointment tins and tested for shelf life stability. Controls were prepared by duplicating the procedure of Example 1 except that no propyl gallate or other antioxidant was dissolved in the ether. The ointments prepared with the use of the propyl gallate showed stability at 50 C. for at least one month whereas'the controls turned brown and discolored after only a few days standing at this temperature. After standing for two months at 50 C. the ointments prepared using the propyl gallate anti-oxidant showed only a very slight tinge of brown. Tins of the ointment which were stored at room temperatures retained their activity without showing any appreciable discoloration for periods in excess of one year.

The epinephrine activity of the various ointments was tested by making scratches on the anterior aspect of the forearm with a binocular loupe and then applying the ointments to the scratches. The ointments undergoing test evalution were applied to one scratch and a freshly prepared control ointment was applied to an adjacent scratch and the blanching reactions observed. This is a delicate and sensitive test for epinephrine stability since Example 4 30 grams of the epinephrine ointment base prepared in accordance with Example 1 was uniformly and intimately blended with 30 grams of benzocaine ointment. The ointment product obtained was useful in the treatment of pruritus due to dermatoses where the skin is broken,

poison ivy, contact dermatitis, pruritis ani, pruritis vulvae and neurodermatitis.

A number of modifications and substitutions may be made in the foregoing examples. Thus, the epinephrine base USP may be replaced with equivalent quantities of epinephrine hydrochloride, epinephrine bitartrate or epinephrine sulfate. The propyl gallate may be replaced by other anti-oxidants which are soluble in the organic liquids used such as ether. Thus, butylated hydroxyanisole, tocopherol (vitamin E), ethyl thioglycollate, and other oil-soluble anti-oxidants may be used in lieu of the propyl gallate in Example 1. In like manner, the ether in Example 1 may be replaced by other solvents such as acetone, chloroform or other compatible volatile solvent.

The mineral oil in Example 1 may be replaced by vegetable oils such as refined castor oil, peanut oil or olive oil. While petrolatum is the preferred ointment base or vehicle, it can be replaced in whole or in part by other ointment bases such as low melting parafiins and substantially water-free vanishing creams.

Apparently, when the suspensions of epinephrine in the anti-oxidant solutions are evaporated in accordance with the method described in Example 1, the anti-oxidants which are in solution form adherent protective coatings or sheaths around each particle of the epinephrine compound so as to keep the epinephrine out of contact with oxygen. These sheaths seem to remain intact to a considerable extent even when the resulting coated particles of the epinephrine are dispersed in the oils or ointment bases. Improved results are obtained when the antioxidant solutions containing the dispersions of epinephrine are not evaporated to complete dryness but are allowed to retain a small residual amount of the volatile solvent thereby preventing the anti-oxidant coated particles of epinephrine from adhering one to another and forming a non-suspendable film or deposit.

Having fully disclosed my invention and set forth preferred embodiments thereof, what is claimed as new is:

l. The method of preparing an oleaginous epinephrine composition which may be exposed to air without substantial loss of epinephrine potency which comprises, dispersing particles of a physiologically active epinephrine compound in a solution of an organic anti-oxidant in an organic solvent in which solution the epinephrine is substantially insoluble, vaporizing the solvent so as to form a solid residue of particles composed of epinephrine and said organic anti-oxidant, and uniformly blending said residue in an oleaginous vehicle.

2. The method of preparing an oleaginous epinephrine composition which may be exposed to the atmosphere without substantial loss of epinephrine potency which comprises, dispersing particles of a physiologically active epinephrine compound in a solution of an organic antioxidant in a volatile organic solvent in which the epinephrine is substantially insoluble, evaporating substantially all of said solvent but discontinuing evaporation before it is complete so as to form a residue which is not completely dry, and uniformly blending said residue in an oleaginous vehicle.

3. The method of preparing an epinephrine ointment which is relatively stable on exposure to air which comprises, dispersing particles of a physiologically active epinephrine compound in a solution of an epinephrine protecting organic anti-oxidant dissolved in a volatile organic solvent in which the epinepherine is substantially insoluble, evaporating said solvent just short of dryness, and uniformly blending the resulting residue in an ointment base.

4. The method of preparing an epinephrine ointment which comprises, dispersing particles of physiologically active epinephrine compound in a solution of an epinephrine protective organic anti-oxidant dissolved in ether, evaporating the ether so as to form a residue which may be pulverized and contains a small amount of ether, uniformly suspending said residue in oil, and blending the resulting oil mixture into an ointment base.

5. The method of preparing an epinephrine ointment which retains its potency when exposed to the atmosphere which comprises, dispersing particles of physiologically active epinephrine in a solution of propyl gallate in ether, evaporating the ether to form a solid residue of particles composed of epinephrine and propyl gallate, uniformly suspending said residue in mineral oil, and blending the mineral oil suspension into petrolatum.

6. Epinephrine ointment which is stable to oxidation comprising particles composed of physiologically active epinephrine and an organic anti-oxidant substance uniformly dispersed throughout an ointment base, said ointment being prepared substantially according to the method of claim 1.

7. Epinephrine ointment stabilized against oxidative deterioration comprising particles composed of physiologically active epinephrine and propyl gallate uniformly dispersed throughout an ointment vehicle, said ointment being prepared substantially according to the method of claim 2.

8. Epinephrine ointment stabilized, against oxidative deterioration comprising particles composed of physiologi- Wilhelm Mar. 13, 1934 Taylor Oct. 22, 1940 6 OTHER REFERENCES I. Pharmacy and Pharmacology, Nov. 1949, pages 774-776.

Gutman: Modern Drug Encyclopedia and Therapeutic 5 Guide, pages 14, 15, New Modern Drugs, N. Y., 1941. 

1. THE METHOD OF PREPARING AN OLEAGINOUS EPINEPHRINE COMPOSITION WHICH MAY BE EXPOSED TO AIR WITHOUT SUBSTANTIAL LOSS OF EPINEPHRINE POTENCY WHICH COMPRISES, DISPERSING PARTICLES OF A PHYSIOLOGICALLY ACTIVE EPINEPHRINE COMPOUND IN A SOLUTION OF AN ORGANIC ANTI-OXIDANT IN AN ORGANIC SOLVENT IN WHICH SOLUTION THE EPINEPHRINE IS SUBSTANTIALLY INSOLUBLE, VAPORIZING THE SOLVENT SO AS TO FORM A SOLID RESIDUE OF PARTICLES COMPOSED OF EPINEPHRINE AND SAID ORGANIC ANTI-OXIDANT, AND UNIFORMLY BLENDING SAID RESIDUE IN AN OLEAGINOUS VEHICLE.
 6. EPINEPHRINE OINTMENT WHICH IS STABLE TO OXIDATION COMPRISING PARTICLES COMPOSED OF PHYSIOLOGICALLY ACTIVE EPINEPHRINE AND AN ORGANIC ANTI-OXIDANT SUBSTANCE UNIFORMLY DISPERSED THROUGHOUT AN OINTMENT BASE, SAID OINTMENT BEING PREPARED SUBSTANTIALLY ACCORDING TO THE METHOD OF CLAIM
 1. 